Interpreting Key Trials

The Women’s Health Initiative: Implications for clinicians

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ABSTRACTThe Women’s Health Initiative (WHI), the largest and longest randomized controlled study to date of the effect of dietary change on disease outcomes in postmenopausal women, failed to show that a low-fat diet prevents breast cancer, colon cancer, or cardiovascular disease. However, as the authors point out, the WHI Extension Study provides opportunities to assess whether nearly significant differences in breast cancer rates at 8 years become significant after 10 years of follow-up.

KEY POINTS

  • Colon cancer rates did not differ between the dietary intervention group and the comparison group, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.
  • Risk factors for coronary heart disease improved slightly with the diet, but by trial year 3, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.
  • When stratified by quartiles, those who reduced their intake of saturated and trans-fatty acids the most, or who increased their intake of fruits and vegetables the most, appeared to have a moderate reduction in the risk of coronary heart disease.


 

References

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).7 Participants were followed at 40 clinical centers between 1993 and 2005.4 Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies8 that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans10 and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire6 to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

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